National Cancer InstituteNational Cancer Institute
The Early Detection
Research Network
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
JANUARY 2008
Division of Cancer Prevention
Investing in Translational Research on
Biomarkers of Early Cancer and Cancer Risk
2 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Contents
5 Foreword
7 Introduction
8 Executive Summary
Part I: Progress and Disease-Specific Developments
14 Chapter 1 Overview
26 Chapter 2 Breast and Gynecologic Cancers
34 Chapter 3 Colorectal and Other Gastrointestinal Cancers
47 Chapter 4 Lung and Upper Aerodigestive Cancers
56 Chapter 5 Prostate and Other Urologic Cancers
Part II: Process and Collaboration
66 Chapter 6 Validation Stages and Processes
77 Chapter 7 Enabling Technologies
Part III: Investing in Biomarker Research
91 Chapter 8 Business Model
99 Chapter 9 Evaluating Biomarker Progress in Translational Research
104 Chapter 10 Investing in Biomarker Research for Early Detection
Appendix
115 I. Key Publications by Investigators
123 II. Publications Co-Authored by NCI Program Staff
124 Glossary

3
4 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Foreword
January 2008
In 2000, NCI’s Division of Cancer Prevention created an investigator-
driven network designed to conduct translational research that identified
markers both for the early detection of cancer and of cancer risk. That
program, the Early Detection Research Network (EDRN), focuses on the
goal of creating validated biomarkers ready for large-scale clinical test-
ing and eventual application. Without a doubt, real progress has been
made—and is being made—by this consortium of more than 300 inves-
tigators and 40 private sector and academic institutions. These scientists
represent divergent disciplines, including genomics, proteomics, metabo-
lomics, bioinformatics and public health.
EDRN is at the forefront of technology-driven research on the use of
biomarkers for the early detection of cancer. By identifying and validat-
ing biomarkers, such as novel proteins or changes in gene expression, it
is possible to measure an individual’s disease risk, progression of disease,
or response to therapy. Ultimately, EDRN research will aid in prevention
and in early therapeutic intervention, based on early detection of disease.
Researchers with EDRN have been instrumental in identifying and
validating markers for many major cancers, such as prostate (protein
profiling of BPH, HPIN and IGFb3/br), colon (K-ras mutations in stool
and urine) and breast (alpha catenin genes). They have also joined forces
with clinical trial communities to accelerate biomarker validation. To
take just one example, EDRN investigators work with investigators in
the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening
Trial and in the Specialized Programs of Research Excellence (SPORE)
program, to test a panel of biomarkers for ovarian cancer in sera collected
in the PLCO trial.

Early detection can dramatically improve outcomes. Finding breast and
colon cancers when they remain localized results in 5-year survival rates
of 90 percent or higher. EDRN is helping make that an achievable goal
for more and more cancers.
John Niederhuber, M.D.
Director
National Cancer Institute
National Institutes of Health
Foreword 5
NCI’s Division of Cancer Prevention set out 7 years ago to create a
strong, investigator-driven network to conduct translational research to
identify tests for early cancer and cancer risk. In 2000, the Early Detec-
tion Research Network (EDRN) became a fully funded group of 28
grantees focused on the overarching goal of creating validated biomarkers
ready for large-scale clinical testing.
Today, EDRN is a nationwide, interdisciplinary group of established
partnerships among scores of institutions and hundreds of individuals
working to advance the science for public benefit.
These research collaborations take place within an environment of team-
work across different disciplines and laboratories focused on achieving
common goals, such as:
• Developing and testing promising biomarkers and technologies to ob-
tain preliminary information to guide further testing;
• Evaluating promising, analytically proven biomarkers and technologies,
such as measures of accuracy, sensitivity, specificity and, when possible,
as potential predictors of outcomes or surrogate endpoints for clinical
trials;
• Analyzing biomarkers and their expression patterns to serve as back-
ground for large, definitive validation studies;

• Collaborating with academic and industrial leaders to develop high-
throughput, sensitive assay methods;
• Conducting early phases of clinical and epidemiological biomarker
studies; and
• Encouraging collaboration and dissemination of information to ensure
progress and avoid fragmentation of effort.
EDRN is a leader in defining and using criteria for the validation of
biomarkers—an essential condition for scientific progress. While myriad
proteins and genes have been linked with a variety of cancers, acceptable
biomarkers must be: reliable and repeatable in testing; highly sensitive
and specific; quantitative; readily obtained by non-invasive methods; part
of the causal pathway for disease; capable of being modulated by the che-
mopreventive agent; and have high predictive value for clinical disease.
EDRN is helping translate the discovery and validation of biomarkers to
clinical use and we are delighted to be working toward that end.
Peter Greenwald, M.D., Dr.P.H., Director
Division of Cancer Prevention, National Cancer Institute
Assistant Surgeon General, U.S. Public Health Service
Introduction
Introduction 7
The National Cancer Institute (NCI) is
bringing visionary people together through
research collaborations that inspire innovative
approaches to early detection, prevention and
treatment of cancer.
NCI launched the Early Detection Research
Network (EDRN) ( in
2000 to identify biomarkers, substances found
in blood, body fluids or tissue that show the
risk or presence of disease before cancer has

had the opportunity to progress in the body.
EDRN is the only program focused directly
on the discovery and validation of biomarkers
for noninvasive, early detection of cancer.
The Network unites clinical and basic
scientists so that discovery is clinically driven,
yet balanced with a systematic approach
to validation.
Recent reductions in cancer mortality are
due in part to risk reduction behaviors like
smoking cessation and more strongly to early
detection of cancer coupled with appropriate
therapy. Yet, there are no validated molecular
biomarker tests for the early detection of any
cancer (see Table I). Among the list of Food
and Drug Administration (FDA)-approved
biomarkers, none have been approved for
cancer early detection and screening. EDRN
is studying more than 120 biomarkers for the
major organ system groups (see Table 2), some
of which are in Phase 3 testing, a retrospective
longitudinal approach that determines how
well biomarkers detect preclinical disease
by testing them against tissues collected
longitudinally from research cohorts.
Investigators from more than 40 research
institutions are part of the Network. All
share a common belief that the integration
of discovery, evaluation and clinical validation
phases of medical research are more likely

to succeed when they are carried out in a
concerted and systematic fashion. A common
problem is that after researchers discover
biomarkers, the biomarkers are not produced
for clinical use because they have not been
validated in other laboratories. To address this,
EDRN drew up and implemented standards
to accelerate the progress for discovering
and validating reproducible biomarkers that
ultimately can be moved on to clinical use.
Through cooperative agreement awards, NCI
is closely involved in the EDRN projects
to ensure the studies gather necessary data.
EDRN welcomes other interested researchers
to join the Network through smaller scale
Table 1. Early Detection Tests
for Cancer, Selected Organ Sites
Organ Site Test
Bladder None
Breast Mammogram
Cervix Pap smear
Colorectal Fecal occult blood test,
sigmoidoscopy, colonoscopy,
double contrast barium
enema, digital rectal exam
Esophageal None
Kidney None
Liver (primary) None, but two molecular
tests are approved for risk
assessment

Lung Imaging
Ovary None proven to decrease
mortality
Pancreatic None
Prostate None proven to decrease
mortality
Executive Summary
8 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
projects. The Network is challenged to
motivate scientists to offer their candidate
biomarkers for testing and to educate
scientists about the importance of rigorous
prevalidation studies that prepare the way for
successful biomarker validation.
This report, the fourth in a series, summarizes
the major developments in the Network since
its inception through a discussion of concepts
and concrete examples, beginning with a
historical and structural overview. It also
shows how progress has occurred in the areas
of:
• Disease-specic advancements across the
major organ sites;
• Process and collaboration; and
• An adaptive business model approach that
encourages public-private partnerships and
team science.
Disease-Specific Advancements
EDRN has active ongoing work in cancer
sites that constitute nearly 1 million cancer

diagnoses each year and more than 350,000
deaths.
Biomarkers in development by EDRN
address common malignancies as well as
mesothelioma and hepatocellular cancer.
The latter are of major worldwide importance
and are increasing in incidence in the United
States. EDRN Collaborative Groups,
focused on breast and gynecologic cancers,
gastrointestinal and other associated cancers,
lung and upper aerodigestive cancers and
prostate and urologic cancers, each have
biomarkers in prevalidation and validation
phases in which the accuracy of experimental
results is confirmed.
There are over 120 biomarkers in
development, alone and in combinations,
across the EDRN phases: 27 in Phase 2
development (validating the capacity of
biomarkers to distinguish between people with
cancer and those without), of which, more
than 15 are progressing toward Phase 3; and
five in Phase 3 development (determining the
capacity to detect preclinical disease).
Highlights of EDRN achievements include:
• Standard reference specimens and reagents,
primarily plasma and serum (cases and
matched controls) were developed for
detection and evaluation of prostate cancer
biomarkers; urine reference sets are being

developed for bladder, prostate, colon and
lung cancers.
• Recurrent non-random chromosomal
translocations were discovered in prostate
cancer along with some other potential
markers, such as %proPSA, PCA3,
AMACR and a panel of autoantibodies;
panels of methylated DNA sequences and
other biomarkers have been identified
as promising biomarkers for bladder
and prostate cancers; and mutations and
deletions in mitochondrial DNA were
detected in prostate and other cancers.
• Molecular tests for ovarian cancer are
progressing towards validation; one of
the tests included a panel of markers
consisting of MIF-1, prolactin, osteopontin,
IGF-2, leptin, HE-4 and others. Studies are
underway targeting pre-cancers of the cervix
to improve outcomes and reduce treatments;
and novel strategies against breast cancer,
including early detection using blood
markers, will be tested in the next year.
Table 2. Early Detection Biomarkers in
Study for Selected Cancer Sites 2003
to 2007 (partial list; see organ specific
chapters for details)
Site Number of Biomarkers *
Bladder 3
Breast 7

Cervical /Endometrial 2
Colorectal 21
Esophagus 7
Hepatocellular 9
Kidney 1
Lung 12
Mesothelium 2
Ovarian 5
Pancreatic 16
Prostate 15
* Panels including more than one biomarker were counted
as one.
Executive Summary 9
• For each digestive cancer organ site (colon,
rectum, esophagus, liver and pancreas), new
biomarkers have been discovered and, in
prevalidation studies, have been shown to be
superior to current standards of care. Two
of these biomarkers for colorectal cancer,
CCSA-2 and CCSA-3 and two biomarkers
for liver cancer, DCP and AFP-L3, are now
in clinical validation.
• Work is advancing to identify and validate
non-invasive biomarkers in blood or sputum
for the early detection of lung cancer, which
could be combined with CT scanning of
the lung or other imaging methods. In two
preliminary blinded experiments, a panel
of only two marker genes readily identified
lung cancers at specificity and sensitivity

values exceeding those of conventional
cytology by two to three times.
• Investigators supported through various
funding mechanisms (e.g., EDRN, R01,
P01 and Specialized Programs of Research
Excellence (SPOREs) ) have formed a
Lung Cancer Biomarkers Working Group.
This group is developing and validating
proteomics-based biomarkers for early
detection of lung cancer and collaborating
with other researchers by providing
statistically powered specimen sets for rapid
evaluation of emerging technologies and
biomarkers.
Some biomarker discoveries are performed
in tandem with prevalidation studies using
high-quality specimens made available
to investigators by other NIH supported
programs, such as the Women’s Health
Initiative (WHI) for a colon cancer project;
the Carotene and Retinol Efficacy Trial
(CARET) for a lung cancer and mesothelioma
project; and the Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial (PLCO)
for an ovarian cancer project. Leads on other
biomarkers from model systems are being
tested in humans.
Process and Collaboration
Validation of biomarkers is a formidable task,
which needs a consistent approach. EDRN-

supported validation studies are, therefore,
remarkable achievements. Few biomarkers
and developmental laboratories ever achieve
the requirements necessary to conduct such
studies. But EDRN brings to the table
both the scientific paradigm and the ability
to effectively organize the resources. Five
case-control studies described in this report
illustrate this capacity. EDRN also adopted
criteria to prioritize analytical and clinical
validation studies.
Quality assurance is integral to EDRN. The
Network established five Biomarker Reference
Laboratories (BRLs) to support clinical and
analytical validation efforts: the University of
California, Los Angeles (UCLA), University
of Alabama, Birmingham (UAB), Johns
Hopkins University (JHU), the University of
Maryland (UM) and the National Institute
of Standards and Technology (NIST). The
BRLs are important resources for technology
development, standardization of biomarkers
and the refinement of existing methods. Some
BRL projects include:
• Validation of bleomycin-induced
chromosomal breakage in lymphocytes as
markers of lung cancer susceptibility;
• Validation of mitochondrial DNA mutations
as an early detection marker;
• Development of high-density breast and

prostate tissue microarrays;
• Validation of saliva-based assay for oral
cancer, refinement of ELISA-based assay for
ovarian biomarker panel;
• Validation of standard operating procedures,
MSA assays, methylation assays; and
• Validation of several prostate-specic
biomarkers, assays and proteomics-based
discoveries.
EDRN develops and optimizes technologies
for biomarker research. Innovative methods
to identify gene alterations, gains and
mutations and mitochondrial DNA mutations
have been used. Proteomics, auto-antibodies,
microsatellite analyses, immunohistochemical
markers, polymerase chain amplification of
RNA and glycobiology are also employed.
Advances were made in deploying and
expanding an informatics framework to
support information management. Accessing
the information includes specific annotations
of markers, the capture of scientific data,
management of the study-specific information
10 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
and a scientific portal. A major new release
integrated with a scientific portal was
deployed in 2007.
One of the signature accomplishments of
the informatics team is the development
of common data elements (CDEs) for use

among the EDRN Clinical Epidemiology and
Validation Centers (CEVCs). CDEs capture
and share data among centers. State-of-the-
art methods that previously did not exist
have been established for data elements, e.g.
acquisition and storage of biologicals, study
design, outcome assessment and biomarker
validation.
Each EDRN institution within the knowledge
system uses CDEs to describe critical cancer
data objects and to map their local data
models to the Network’s knowledge system,
in turn providing Network-wide semantic
consistency. At the same time, the EDRN
Network Exchange system (ERNE) unified
search and retrieval of biospecimen data
from all institutions regardless of their
location, how it is stored, or the differences
in the underlying data models. This enables
a scientist, for example, to locate tissue
specimens for breast cancer by searching data
catalogs at participating EDRN institutions
across the country.
EDRN-supported statistical tools and
informatics infrastructure make the sharing
of samples, the developing of collaborations
and the exchanging of information with the
extramural community at-large, both feasible
and productive. The EDRN informatics
efforts were cited as a model in reports by

the National Academy of Sciences Institute
of Medicine, Developing Biomarker-Based
Tools for Cancer Screening, Diagnosis and
Therapy: The State of the Science, Evaluation,
Implementation and Economics (Margie
Patlak and Sharyl Nass, 2006) and Cancer
Biomarkers: The Promises and Challenges of
Improving Detection and Treatment, (Sharyl J.
Nass and Harold L. Moses, Editors, 2007).
EDRN developed a secure, web-based
system, the Validation Studies Information
Management System (VSIMS), to manage
the necessary components for capturing and
preserving the metadata and data objects that
integrate into the overall knowledge system
architecture. These components include
protocol management tools, communication
tools, a data-collection and -processing system
and a specimen-tracking system.
EDRN is establishing a science data
warehouse, which will act as a distributed
metadata-driven system to capture, track,
process and retrieve scientific data from
biomarker validation studies and to share
across institutions. The EDRN Knowledge
System promises to dramatically improve the
capability for scientific research by enabling
real-time access to a variety of information
across research centers.
Adaptive Business Model

The core of EDRN’s achievements is
the Vertical Adaptive Business Model.
This structure encourages public-private
partnerships and team science. EDRN
promotes a vertical approach for conducting
biomarker research, whereby biomarkers
are developed in BDLs, refined and cross
validated by Biomarker Reference Laboratories
(BRLs) and validated in collaboration with
CEVCs, all within one organization. The
focus is on coordinating multiple resources
with a goal of minimizing the barriers to
the rapid and efficient “hand-off” between
entities.
Five federal agencies—NIST, the Centers for
Disease Control and Prevention, FDA, the
Pacific Northwest National Laboratories of
the Department of Energy and the National
Aeronautics and Space Administration (NASA)
Jet Propulsion Laboratory (JPL)—participate
with EDRN through interagency agreements.
Other intergovernmental collaborative
partnerships include the National Heart,
Lung and Blood Institute (NHLBI) on the
use of the Women’s Health Initiative (WHI)
biorepository for discovery and validation
of biomarkers; the collaboration with the
Consortium of Functional Glycomics, funded
by National Institutes of Health’s (NIH)
National Institute of General Medical Sciences

(NIGMS) and four carbohydrate research
centers funded by NIH’s National Center
for Research Resources (NCRR).
Executive Summary 1110 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
EDRN unites partners with different
research foci, resulting in productive and
stable alliances to expedite discovery and
development of biomarkers and technologies.
For instance, JPL, known for rocket
launching, joined forces with EDRN to bring
disparate groups of institutions together
by creating virtual resources of specimens,
biomarkers, tools and technologies,
through innovative uses of their informatics
infrastructures already validated and proven
for the management of planetary data.
Another unlikely alliance is NIST and EDRN.
NIST is traditionally known for research
on physical sciences and standards, not for
diagnostics. By joining EDRN, NIST has
taken an interest in developing standards for
genomics- and proteomics-based diagnostics.
EDRN fosters collaborations with industry.
During its inception, EDRN worked with
NCI’s Technology Transfer Center to develop
novel methods for sharing confidential
information with industry and EDRN’s
Technology Resources Sharing Committee
developed guidelines for working with
industry. EDRN also conducted a workshop

on public-private partnerships. Collaborations
with the Human Proteome Organization on
proteomics and glycomics, the Lustgarten
Foundation on pancreatic cancer biomarkers
and the Canary Foundation on ovarian cancer
markers are yielding results.
EDRN enables alliances of investigators
with differing expertise, disciplines and
organizational cultures to function as
cohesive, integrated groups for the purpose
of developing biomarker-based diagnostics.
This Network of discovery, validation and
epidemiologic centers that place collective
goals above individual goals is without
peer among academic institutions. Unlike
previous approaches in the field, EDRN
rewards collaboration and individual skills
and thereby is likely to succeed in meeting the
new research realities involved in translational
research.
EDRN builds standards in study designs for
the systematic evaluation of protein profiling
for cancer. The Network developed standards
of organization and collection for tissue
procurement for biomarker studies. Aspects
of the standards are recognized as best
practices in the field for sharing and
dissemination within an informatics network
exchange system (National Biospecimen
Network Blueprint from the Constella Group

and the Case Studies of Human Tissues
Repositories: “Best Practices” for Biospecimen
Resource for Genomic and Proteomic Era
(Eiseman E., et.al., RAND Corporation)).
The number of peer-reviewed publications by
EDRN-funded investigators is an important
metric to illustrate progress toward the
Network’s goals. More than 460 manuscripts
have been published by EDRN investigators
and program staff in the past 6 years. Seminal
articles on proteomics, fusion genes in the
prostate and methylation have received wide
citations.
When EDRN was created, NCI embarked
on a new organizational structure unique
to academic science. EDRN created a
rigorous peer-review system that ensures
that preliminary data—analytical, clinical
and quantitative—are of excellent quality.
Additionally, the Associate Membership
Program is highly productive in offering new
technologies and products.
Past, Present, Future
The progression of biomarkers from the
discovery phase to the validation phase has
been slow to date, reflecting initial challenges
with cultural and infrastructural issues.
Without EDRN, research into new
biomarkers of early cancer detection and
risk would have remained on the periphery

of research with a strong, but fragmented
laboratory presence and little translational
interest among the academic scientific
community. But with the Network, a new
translational paradigm is defining the
organization, approaches and standards by
which biomarkers are developed and assessed.
The Network’s publications, meetings,
funding opportunities and infrastructure
have fashioned a new environment for cancer
prevention research.
12 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Title of chapter goes here 13
Part One
Progress and Disease-
Specific Development
12 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
I
N ITS FIRST 7 YEARS, the Early
Detection Research Network (EDRN)
evolved from ground-breaking concept
to operational success. With a primary
mission to discover and scrupulously validate
biological markers that signal the earliest
stages of cancer (such as pre-malignant lesions,
genetic variations and risk indicators) EDRN
combines collaborative and multidisciplinary,
investigator-initiated projects with a strong
administrative and data infrastructure.
In making cancer biomarkers of early

detection and screening ready for large-scale
clinical testing, the Network requires and
supports collaboration and information
sharing across institutions. Key milestones
from inception to the present are described in
this chapter.
1997 through 2000:
Inception and Inauguration
In 1997, a 20-member Cancer Prevention
Program Review Group, seeking a means to
revitalize the National Cancer Prevention and
Control Program, recommended the concept
of EDRN to NCI’s Board of Scientific
Advisors (BSA) and the National Cancer
Advisory Board (NCAB). (See EDRN Initial
Report, Translational Research to Identify Early
Cancer and Cancer Risk, October 2000, http://
edrn.nci.nih.gov/docs.)
The concept, developed by the Early
Detection Implementation Group, was
approved by the BSA on November 13,
1998. A Network was envisioned that would
discover and coordinate the evaluation of
biomarkers and reagents for risk assessment
Overview
“T
he EDRN was designed with a very specific and tangible goal in mind. This
has not changed since its inception. For this reason, the network is efficient and
functions true to its origin. Further, since it is fully functional, there is little effort
wasted on operational issues. The operations manual was adopted early and

remains a viable document. Under any context, these are remarkable properties,
that it was created by a governmental agency is nearly unimaginable. With
academic scientists and clinicians working under cooperative agreements, not
contracts, to specifically further the goals of the network, not just their personal
goals, the arrangement becomes even more unlikely.”
Jeff Marks, Ph.D.
Principal Investigator,
EDRN Biomarker Development Laboratory
Duke University Medical Center
14 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
CHAPTER ONE
Title of chapter goes here 1514 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Recent Milestones*
March 2003 EDRN Approved for Second 5-Year Cycle
July 2003 Validation Study Launched: SELDI Profiling for Prostate Cancer
August 2003 Gordon Conference on New Frontiers in Cancer Detection and Diagnosis, Andover, NH
September 2003 Launch of the First Clinical Validation Study for Microsatellite Instability as a Biomarker for Bladder Cancer
March 2004 Training Workshop on the Analysis of Proteomic Spectral Data including SELDI/MALDI-TOF-MS Applications;
Review of SELDI Phase 1, Seattle, WA
June 2004 Third Annual Scientific Workshop, Bethesda, MD
September 2004 EDRN Outreach Meetings:
Breast/GYN Collaborative Group Meeting, New York, NY
GI Collaborative Group Meeting, Norfolk, VA
GU Collaborative Group Meeting, Houston, TX
Lung Collaborative Group Meeting, Denver, CO
January 2005 Gordon Conference on New Frontiers in Cancer Detection and Diagnosis, Santa Barbara, CA
March 2005 Tenth Steering Committee Meeting, Bethesda MD
September 2005 Eleventh Steering Committee Meeting, Seattle, WA
August 2005 NIST-EDRN Workshop on Standards and Metrology for Cancer Diagnostics, Gaithersburg, MD
January 2006 EDRN Pancreatic Implementation Meeting, Denver, CO

February 2006 EDRN Lung Implementation Team Meeting, Rockville, MD
March 2006 Twelfth Steering Committee Meeting and 4th Annual Scientific Workshop, Philadelphia, PA
September 2006 Thirteenth Steering Committee Meeting, Pittsburgh, PA
October 2006 EDRN and Hepatitis B Foundation Workshop, Princeton, NJ
January 2007 Gordon Conference on New Frontiers in Cancer Detection and Diagnosis, Ventura, CA
February 2007 EDRN FDA Education Workshop Bethesda, MD
March 2007 Fourteenth Steering Committee Meeting, Denver, CO
April 2007 AACR Session on Novel Technologies and Validation Challenges, Los Angeles, CA
May 2007 NCI Division of Cancer Prevention Workshop on Cancer Stem Cells as Targets for Cancer Prevention
and Early Detection, Bethesda, MD
* See previous reports for earlier milestones.
and early detection of cancer in primary
organ systems, such as prostate, breast, lung,
colorectal and upper aerodigestive tract. To
accomplish this vision, the Network would:
• Develop and test promising biomarkers and
technologies in institutions with outstanding
scientific and clinical expertise;
• Evaluate promising biomarkers for
diagnostic predictive accuracy, sensitivity,
specificity and medical benefits;
• Develop molecular and expression markers
to serve as background information for
subsequent large definitive validation
studies of detection and screening
biomarkers;
• Coordinate academic and industrial leaders
in molecular biology, molecular genetics,
clinical oncology, computer science, public
health and other disciplines to develop high-

throughput, sensitive assay methods;
• Conduct early phase clinical and
epidemiological studies to evaluate the
predictive value of biomarkers; and
• Encourage collaboration and rapid
dissemination of information among
participants to aid progress and avoid
fragmentation of efforts.
A structure emerged (see Figure 1-1)
with working components comprised of
laboratories and validation centers and data
management centers and two oversight
components, a Steering Committee and a
Network Consulting Team. The business
model for this structure is discussed in
Chapter 8.
Figure 1-1. Infrastructure of the Early Detection Research Network
This schematic outlines the EDRN infrastructure for supporting translational research on
molecular biomarkers for cancer detection and risk assessment.
Working Groups
Associate
Members
Steering
Committee
Biomarker
Reference
Laboratories
Biomarker
Developmental
Laboratories

Clinical
Epidemiology
and Validation
Centers
Informatics
Center
Data Management
And Coordinating
Center
Collaborative
Groups
Breast and Gynecologic
Subcommittees/
Taskforces
Colorectal and Other
Gastrointestinal Cancers
Lung and Upper
Aerodigestive Tract
Prostate and Other
Genitourinary
T
r
a
n
s
l
a
t
i
o

n
a
l

R
e
s
e
a
r
c
h
16 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
The Biomarker Developmental Laboratories
(BDLs) were designed to develop and
characterize new biomarkers, or refine
existing biomarkers, by conducting active
translational research in the biology of
cancer formation. It was expected that
discoveries would move from laboratory to
clinical and population research settings and
that observations from these settings would
move back to the laboratory for further
refinements as needed.
The Biomarker Reference Laboratories
(BRLs) were planned to serve as a resource
for both laboratory and clinical validation
of biomarkers, in the areas of technology
development, standardized assays and
methods, refinement and high-throughput

operations. BRLs were also responsible for
instituting quality control for reagents and
technologies.
The Clinical Epidemiology and Validation
Centers (CEVCs) were established to
conduct and support early phases of clinical
and epidemiological research on biomarker
applications. Approved projects were soon
started to look at a range of issues, including:
resources and methods for rapid clinical
evaluation of risk and disease biomarkers;
defining molecular signatures predictive of
neoplastic progression in cervical lesions;
clinical utility of certain prostate cancer
biomarkers; developing and maintaining a
registry of individuals harboring germline
mutations for hereditary cancer syndromes;
and identifying preneoplastic lesions and
early cancer in populations at risk due to
environmental and occupational exposures.
To manage the flow of information across
the network, the Data Management and
Coordinating Center (DMCC) and an
Informatics Center, managed by the Jet
Propulsion Laboratory (JPL) at the National
Aeronautics and Space Administration
(NASA) were established. These entities were
designed to support statistics, logistics and
informatics and develop theoretical statistical
approaches for pattern analysis of multiple

biomarkers simultaneously. DMCC also
coordinates network-wide meetings and
conferences and serves as the Coordinating
Center for validation studies. (See Margaret
Sullivan Pepe, The Statistical Evaluation of
Medical Tests for Classification and Prediction,
Oxford Statistical Science Series Number 28,
Oxford University Press, 2003.)
A Steering Committee, comprised of the
Network’s Principal Investigators and
NCI staff, was formed to coordinate the
work of the consortium and provide major
scientific and management oversight, such as
developing and implementing protocols, study
designs and general operations.
An ad hoc Network consulting team of
non-EDRN investigators was instituted to
recommend new research initiatives and to
ensure Network responsiveness to promising
research opportunities. Members of the group
have reviewed EDRN as part of the external
evaluation process.
Biomarker Reference Laboratories in 2008
These laboratories serve as a Network resource for clinical and laboratory validation of biomarkers.
Principal Investigator Location
Dan Chan, Ph.D. Johns Hopkins Medical Institutions
David Chia, Ph.D. University of California, Los Angeles
Miral Dizdar, Ph.D. National Institute of Standards and Technology
William E. Grizzle, M.D., Ph.D. University of Alabama at Birmingham
Karin Rodland, Ph.D. Pacific Northwest National Laboratory

Sanford Stass, M.D. University of Maryland School of Medicine
Overview 17
18 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Early Challenges
Establishing and sustaining collaborations
while ensuring a smooth flow of discoveries
from the laboratory to the clinic were clearly
key challenges to the nascent Network.
Efforts focused on developing methods for:
• novel approaches to validation studies
during the early stages of investigation;
• improved informatics and information flow
using new systems for data organization and
sharing;
• standardized data reporting by creating a
dictionary of neoplastic and pre-neoplastic
events and common data elements (CDE)
for biomarkers;
• statistical and computational tools; and
• standardized reagents and assays.
Biomarker Development Principles
The Network developed systematic,
comprehensive guidelines to develop, evaluate
and validate biomarkers. This five-phase
approach established both a scientific standard
and a roadmap for successfully translating
biomarker research from the laboratory to the
clinic.
Phase 1 – discovery, involves exploratory
study to identify potentially useful

biomarkers.
Phase 2 – validation, occurs where biomarkers
are studied to determine their
capacity for distinguishing between
people with cancer and those
without.
Phase 3 – determines the capacity of a
biomarker to detect preclinical
disease by testing the marker against
tissues collected longitudinally from
research cohorts.
Phase 4 – includes prospective screening
studies on biomarker performance
in large populations and determines
its false referral rate.
Phase 5 – suggests the penultimate period
in which large-scale population
studies evaluate both the role of the
biomarker for cancer detection and
its overall screening impact.
Although the Network’s focus is mainly
on Phases 1 through 3, researchers have
welcomed the five-phase structure because
it provides an orderly succession of studies
that build upon each other to yield an
efficient and thorough approach to biomarker
development.
Project Prioritization
The Network implemented guiding principles
for biomarker validation and used criteria

developed by the Review Group to prioritize
the first round of proposals for collaborative
projects. These principles were:
1. Biologic rationale/strength of hypothesis
2. Strength of design
3. Technical parameters
4. Clinical or scientific impact
5. Portfolio balance
6. Practicality
7. Collaborative strength/team effort
Individual grantees brought to the Network a
diverse assortment of potential biomarkers for
development. Projects ranged from biomarkers
for lung carcinoma and pre-malignancy to
cancer risk prediction by mutational load
distribution. Some investigators were seeking
to detect pre-clinical cancer across a range
of organ sites (prostate, liver, ovarian, breast,
lung, colorectal) by protein signatures in
body fluids using novel technologies such
as mass spectrometry and laser capture
microdissection. The BRLs set out to validate
molecular cytogenetic and automated
cytometry assays involving slide-based analysis
of chromosomes as a first step to further
standards setting.
Collaborative Groups and Associate
Memberships
To broaden the opportunities for scientific
interactions and coordinated research,

Collaborative Groups were formed. These
organ-specific research groups were structured
to promote information exchange on organ-
related biomarkers and to identify research
priorities within EDRN.
One major role of the Collaborative Groups
was to serve as advisors/liaisons with Associate
Members. The Associate Membership
component was designed for investigators
who are not affiliated with EDRN but wish to
join the Network by proposing collaborative
studies within its scope and objectives.
Three categories for Associate Membership
were established:
• Category A – domestic or foreign
investigators who propose to conduct basic
or translational research consistent with the
priorities of EDRN;
• Category B – domestic or foreign
members who contribute to the Network
by sharing available technologies and
supplying specimens, making available
high-risk registries and cohorts and other
complementary resources;
• Category C – domestic or foreign
corresponding members who are scientists,
organizations, clinicians, patient advocates,
or ethicists interested in participating in
Collaborative Group meetings, workshops
and conferences, without EDRN funding.

Profile of the EDRN Associate
Membership Program in 2008

More than 151 applications received since 2000

Approximately 40 applications approved

More than 15 diagnostics firms joined as
Category C members

More than 45% of members are new
investigators

More than 60% of Category A members
successfully competed for major grants

Two Associate Members successfully proposed
validation studies
2001 to 2003: Meeting the Scientific
Challenges

Following the principles of systems biology,
in which disciplines like biology, chemistry,
computational science and clinical sciences
are integrated seamlessly, the Network made
strides in meeting the scientific challenges
of biomarker research. The first round
of proposals for collaborative studies was
approved and Steering Committee meetings
convened to continue managing the formation

of the new Network. (See EDRN Second
Report, Translational Research to Identify
Early Cancer and Cancer Risk, October 2002,
/>Discovery Phase
EDRN began actively identifying potential
biomarkers and making inroads for testing
and evaluating usability in early detection
and risk indication. Promising results were
attained, such as:
• Lysophosphatidic acid (LPA) was found to
be promising as a biomarker and further
studies were performed at the discovery
laboratories. LPA is elevated in the plasma of
women with ovarian cancer including 90%
of women with stage I disease.
• A ligand or binding protein for Galectin-
3 was pursued at the Great Lakes New
England Clinical Epidemiology and
Validation Center, which identified the
binding protein in circulating blood.
Galectin-3 is a protein related to tumor
progression and was found to be a
hepatoglobin-related protein, present in
higher concentrations in patients with
colon cancer when compared to those with
precancerous polyps or normal subjects.
• A positive finding that androgen receptor-
length polymorphism is associated with
prostate cancer risk in Hispanic men was
made.

• A progression model for bladder cancer was
developed.
• The result of an extensive search of gene
and protein expression data generated
through two-dimensional gel profiles, mass
spectrometry, quantitative protein data and
gene expression data, found two proteins,


Overview 19
20 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Annexin-1 and Annexin-2, to be candidate
biomarkers for lung cancer (Proc Natl Acad
Sci USA. 2001 98:9824-9). Further validation
studies are ongoing.
• Discussions concerning the informatics
needs of EDRN were conducted and plans
for building the infrastructure began.
Prototypes of the EDRN Network Exchange
system (ERNE), EDRN Task Management
Software, EDRN Statistical Software and the
EDRN secure site were produced and tested.
Guidelines Set for Measuring Biomarker
Predictive Power
To prepare for the next level of investigation,
the Network developed guidelines for
statistical design and analysis of nested case-
control studies on serially collected blood
or tissue specimens. These guidelines, listed
below, are used by researchers designing

studies to measure the predictive power of a
biomarker:
• For clearest interpretation, statistics should
be based on false- and true-positive rates,
not odds ratios or relative risk.
• To avoid over-diagnosis bias, cases should
be diagnosed as a result of symptoms rather
than on screening.
• To minimize selection bias, the spectrum of
control conditions should be the same in the
study and target screening populations.
• To extract additional information, criteria
for a positive test should be based on a
combination of individual markers and
changes in marker levels over time.
• To avoid over-fitting the data, the criteria for
a positive marker combination developed in
a training sample should be evaluated against
random samples from the same study and,
if possible, validation samples from another
study.
Critical Challenges Faced
The interdisciplinary teams of investigators
tackled the critical challenges identified at
the beginning: novel approaches to validation
studies; advanced informatics and information
flow; standardization of reagents and assays
and data reporting; and creation of standard
statistical and computational tools (see Part II).
New approaches to validation studies were set

in motion with preliminary studies in:
• detecting promoter methylation as a risk
marker;
• chromosomal breakage as a marker of lung
cancer susceptibility and early lung cancer
detection using Fluorescence in Situ
Hybridization (FISH);
• mutations in mitochondrial DNA and
telomerase activity as early detection
markers; and
• microsatellite instability as an early
detection marker for bladder cancer.

“T
he EDRN’s goals are ambitious and admirably attempt to perform and
deliver from both ends of the linear biomedical industries world: to discover
new early disease biomarkers and deliver them to the public for use. As if this
was not enough, this is to be done across a range of different cancers.”
Tim Block, Ph.D.
Principal Investigator
EDRN Biomarker Development Laboratory
Drexel University College of Medicine
EDRN Liaisons to Professional
and Scientific Organizations
American Association for Cancer Research
(AACR): William Bigbee, Ph.D.
American College of Obstetricians and
Gynecologists (ACOG): Daniel Cramer, M.D.
American Society for Investigative Pathology
(ASIP): Elizabeth Unger, M.D., Ph.D.

American Society of Clinical Oncology (ASCO):
Dean Brenner, M.D.
American Society of Preventive Oncology (ASPO):
Dean Brenner, M.D.
American Urological Association (AUA):
Alan Partin, M.D., Ph.D.
Cooperative Family Registries: John Baron, M.D.
Human Proteome Organization (HUPO):
Samir Hanash, M.D., Ph.D.
European Organization for Research and
Treatment of Cancer (EORTC): Angelo Paradiso,
M.D., Maria Diadone, Ph.D.
Mouse Models of Human Cancers Consortium:
Jeffrey Marks, Ph.D.
Pharmaceutical and industrial relations:
Wendy Patterson, Esq.
Specialized Programs of Research Excellence
(SPORE) Groups: Adi Gazdar, M.D.
Cooperative Groups: Ian Thompson, M.D.
Union Internationale Contre le Cancer
(International Union Against Cancer):
Michles Bodos, M.D.
2003 to 2004: Network Surges Ahead
NCI supported more than 100 collaborative
projects that spanned the organ sites. BDLs
investigated biomarker candidates for major
organ sites while the first clinical validation
study, microsatellite instability as a biomarker
for bladder cancer, commenced in September
2003. EDRN’s portfolio expanded, its

collection of sample sets and reference data
sets grew markedly and standard tools and
resources were widely utilized. (See EDRN’s
Infrastructures were built to improve
informatics and information flow across the
Network. A public web site and a secure
web site contained general and specific
information about upcoming events, contacts
for institutions and committees, data from
collaborative studies and approved validation
proposals.
Standardization of data reporting came closer
to reality with the development of CDEs
required for use at Network sites. In addition,
a distribution and computing network, known
as the EDRN ERNE, which allows remote
access to live databases at each Network site
via the secured website, was developed by
JPL and the DMCC. ERNE unifies search
and retrieval of biospecimen data from all
institutions regardless of their location, how
data are stored, or the differences in the
underlying data models.
Exceptional analytical approaches and
methods were developed to generate effective
statistical methodologies and computational
tools. These incorporated pre-analysis data
processing; disease classification; protein
biomarker identification; artificial intelligence
learning algorithms; genomic and proteomic

data mining; and systems screening.
In collaboration with EDRN’s federal
partner, NIST, NCI-supported investigators
continued during this period to standardize
methodologies, refine assays and establish
standard reference materials for biochemical,
molecular and cytologic assays.
EDRN forged partnerships with the private
sector (see Part III). The Network initiated
collaborative projects with other NCI-
supported programs to leverage shared
technology and resources; investigators
published abstracts of their work; and liaisons
to numerous professional organizations were
established.
Overview 21
22 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Third Report, Translational Research to Identify
Early Cancer and Cancer Risk, March 2005,
/>To make resources available for validation
research, a number of technologies were
approved and clinical specimens collected and
pronounced “open access” for collaborative
efforts. In addition, the Network surged
ahead in its partnerships with federal
agencies through joint projects. Also, a series
of workshops, meetings, conferences and
collaborative group “town hall” gatherings
were held to further cement alliances and
share information.

Another unique partnership emerged with
the Plasma Proteome Project Initiative of the
Human Proteome Organization (HUPO),
to evaluate multiple technology platforms,
develop bioinformatic tools and standards for
protein identification and create a database
of the plasma proteome (Proteomics August
2005).
The Network-developed study design for a
systematic evaluation of protein profiling,
in this case using SELDI-TOF for cancer
diagnosis, was published and became a model
that can be applied to any other profile-
based proteomics platforms. Accordingly, the
model was extensively discussed and accepted
throughout the research community (Disease
Markers 2005).
The ERNE knowledge system was deployed
to 10 institutions in early 2003, providing a
common web-based client interface. Creation
of a robust framework called the Validation
Study Information Management System
(VSIMS) was created to allow multiple studies
to be administered efficiently by minimizing
development time with standardization of
information and data management across
multiple activities and research sites.
2005 to 2007: An Investment
in Prevention
The NCI’s Translational Research Working

Group (TRWG) was established in 2005
to evaluate the status of NCI’s investments
in translational research and chart a vision
for the future. TRWG defined translational
research as “research that transforms
scientific discoveries arising in the lab, clinic
or population into new clinical tools and
applications that reduce cancer incidence,
morbidity and mortality” (see Figure 1-2).
Figure 1-2. Translational Research Paradigm as defined by NCI’s Translational Research Working Group
Source: Translational Research Working Group Interim Report to the National Cancer Advisory Board, Envisioning the Future of NCI’s Investment in Translational
Research, June 14, 2006 ( />Lab
Clinic Population
New Tools &
New Applications
Biomarker Development Laboratories in 2008
These laboratories are responsible for development and characterization of new,
or refinement of existing, biomarkers.
Principal Investigator Location
William L. Bigbee, Ph.D University of Pittsburgh Cancer Institute
Timothy Block, Ph.D. Drexel University College of Medicine
Paul Cairns, Ph.D. Fox Chase Cancer Center
Arul M. Chinnaiyan, M.D., Ph.D. University of Michigan
Bogdan Czerniak, M.D., Ph.D. University of Texas M. D. Anderson Cancer Center
Laura J. Esserman, M.D., M.B.A. University of California, San Francisco
Wilbur Alan Franklin, M.D. University of Colorado Health Science Center
Adi Gazdar, M.D. University of Texas Southwestern Medical Center
Samir Hanash, M.D., Ph.D. Fred Hutchinson Cancer Research Center
Michael Hollingsworth, Ph.D. University of Nebraska Medical Center
Ann M. Killary, Ph.D. University of Texas M. D. Anderson Cancer Center

Joshua LaBaer, M.D., Ph.D. Harvard Institute of Proteomics
Alvin Y. Liu, Ph.D. University of Washington
Zvi Livneh, Ph.D. Weizmann Institute of Science
Anna Lokshin, Ph.D. University of Pittsburgh Cancer Instititute
Jeffrey Marks, Ph.D. Duke University Medical Center
Martin McIntosh, Ph.D. Fred Hutchinson Cancer Research Center
Stephen Meltzer, M.D. Johns Hopkins University
Harvey Ira Pass, M.D. New York University School of Medicine
Hemant K. Roy, M.D. Evaston Northwestern Healthcare Research Institute
O. John Semmes, Ph.D. Eastern Virginia Medical School
David Sidransky, M.D. Johns Hopkins University
Michael A. Tainsky, Ph.D. Karmanos Cancer Institute
Richard C. Zangar, Ph.D. Pacific Northwest National Laboratory
Overview 23
Informatics Center in 2008
The Informatics Center supports EDRN’s efforts through software systems development for information
management and flow.
Principal Investigator Location
Daniel Crichton, M.S. NASA Jet Propulsion Laboratory at the California
Institute of Technology
24 T H E E A R LY DETECTION RESEARCH NETWORK: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk
Clinical Epidemiology and Validation Centers in 2008
The Centers conduct clinical and epidemiological research on the medical application of biomarkers.
Principal Investigator Location
Steven Belinsky, Ph.D. Lovelace Respiratory Research Institute
Dean Brenner, M.D. University of Michigan
Daniel Cramer, M.D., Sc.D. Brigham and Women’s Hospital
Paul Engstrom, M.D. Fox Chase Cancer Center
Henry Lynch, M.D. Creighton University
Alan W. Partin, M.D., Ph.D. Johns Hopkins University Department of Urology

William Rom, M.D., M.P.H. New York University School of Medicine
Martin Sanda, M.D. Beth Israel Deaconess Medical Center
Ian M. Thompson, M.D. University of Texas at San Antonio
Elizabeth R. Unger, M.D., Ph.D. Centers for Disease Control and Prevention
Data Management and Coordinating Center in 2008
The Center is responsible for coordinating EDRN activities by developing a common database for the Net-
work, providing logistic support, conducting statistical and computational research and guiding statistical
design and data analyses of validation studies.
Principal Investigator Location
Ziding Feng, Ph.D. Fred Hutchinson Cancer Research Center
Program for Rapid, Independent Diagnostic Evaluation (PRIDE):

which was designed to assist translation to the clinic of novel anticancer therapeutic interventions,
either synthetic, natural product, or biologic, arising in the academic community.

the device pathway developed by TRWG.




Overview 25
The EDRN has achieved several milestones.
The operations manual was proven viable.
Guidelines laying out the criteria and
sequential study designs for justification
of requested resources were provided
to investigators. The fully characterized
Network provides an unparalleled system of
strong scientific collaborations that facilitate
high-quality translational research. The

infrastructure works to ensure that good
biomarkers are promoted without regard
to pecuniary interests. The Network’s
emphasis on inclusiveness allows any scientist,
from academia, industry or government to
participate in EDRN activities, thus ensuring
the best chance for promising markers to
become future medical tools.
The Associate Membership Program,
along with a newly established Program for
Rapid, Independent Diagnostic Evaluation
(PRIDE), continues to ensure inclusiveness
of stakeholders, biomarkers, technologies
and processes all along the EDRN business
model. In late 2006, EDRN announced the
PRIDE ( />notice-files/NOT-CA-07-003.html), as an
administrative means to assist extramural
investigators to successfully conduct
cross-laboratory validation of biomarkers.
Investigators from the diagnostic community
were invited to partner with EDRN to
develop new standards for methodologies,
assays, reagents and tools. This initiative
is expected to expand the capacity of
existing resources and speed development
of diagnostic markers. PRIDE will fill a gap
between discovery and clinical application by
providing independent evaluation of potential
biomarkers developed through various
technology platforms and the assays and

reagents needed to accelerate them to
clinical use.